The effectiveness of barbiturates, mannitol, hypothermia and other new therapeutic approaches to the treatment of global or focal (stroke) cerebral ischemia will be evaluated in a primate intensive care laboratory. These studies will be performed in an environment which parallels that available in hospital intensive care units. Global cerebral ischemia will be obtained by cardiac arrest caused by electrical fibrillation of the heart followed by cardiovascular resuscitation: surgical occlusion of the middle cerebral artery will be used to obtain strokes. Treatment with experimental therapies will begin following the production of the ischemic insult and continue for 48 hours or more with the animals receiving additional required supportive care for up to 10 days. Neurologic status will be recorded daily and neuropathological evaluation of the brain and spinal cord performed. The effect of the treatment protocols on the cardiovascular system will also be evaluated as cardiovascular instability associated with aggressive neuroresuscitation may be the major factor limiting application of neuro-protective therapeutic protocols. Specifically, the influence of large doses of barbiturates on the development of myocardial infarction following acute coronary occlusion will be determined. As other successful neuroresuscitative protocols are evolved, they will also be tested in the focal myocardial ischemia model. This approach, considering both brain and heart, is important since stroke and cardiac arrest frequently occur in patients with generalized arteriosclerotic cardiovascular disease. The major goals of this project consist of the testing and development of protocols designed to reduce the pathological impact of ischemia upon the brain. While we feel that barbiturates might prove to be useful drugs in the clinical context of cerebral ischemia, we do not believe that enough laboratory data exists to embark upon generalized clinical trials with these potentially harmful drugs. Our therapeutic testing of aggressive neuroresuscitative protocols will help to further develop guidelines required for clinical trials with treatments found to be beneficial.